The #NephJC crew landed on #KidneyWk, and the team is back to bring you the science behind the headlines! From Thursday through Saturday, we’ll be sharing selected highlights, focusing on late-breaking clinical trials with simultaneous publications.
For each study, we’ll unpack the findings, limitations, and consider what they could mean for kidney care. Whether you’re joining the meeting or following along online, pull up a chair and join the discussion.
We did this last year (link) with excellent feedback, so we are bringing it back. Swap and Cristina talked about the rationale (mostly FOMO!) and how this was done here.
Day 2 Studies
Ravulizumab in IgA (I CAN) Barratt et al, NEJM 2026
Upacicalcet in Hemodialysis Patients with Secondary Hyperparathyroidism, Kendrik K et al, JASN, 2026
Pentoxifylline for chronic kidney disease in people with diabetes: a meta-analysis of randomized trials, Agarwal et al, NDT, 2026
Studies we do not discuss:
Povetacicept in IgA (RAINIER AIS D08) Barratt et al NEJM 2026 (though this was published it will only make it to KidneyWeek presentation on Saturday, so watch out for it in tomorrow’s edition)
Pentoxiphylline trial baseline data, Leehey et al NDT 2026: the VA PTXRx trial was successfully enrolled with almost 2400 patients. Watch out for the main results to drop in the coming months.
A post hoc analysis from CONFIDENCE demonstrating ~ 40% patients did have apparent treatment resistant hypertension, and the combination empagliflozin-finerenone reduced BP by about 9-11 mm Hg (Agarwal et al, JACC Advances 2026)
Ravulizumab in IgA Nephropathy — Interim Analysis of a Phase 3 Trial
J. Barratt, Y.M.K. Farag, K. Rice, T.J. Cammett, L.A. Inker, H. Trimarchi, A. Bruchfeld, H.J.L. Heerspink, A. Liew,K. Carroll, H. Zhang, S. Norouzi, S. Hou,S. Park, M... P.rez Valdivia, J. Radhakrishnan, Y. Suzuki, B. Schneider, J. Marsala, C. Carrillo‑Infante, S.L. Lake, A.K. Singh, S. Nolan, and R.A. Lafayette, for the I CAN Trial Group
Why was the study done?
IgA takes the center stage on day 2. So, what haven't we discussed about IgA yet? To open the show, we turn to complement, a key driver of inflammation and kidney injury on IgAN. Ravulizumab binds complement protein C5, preventing formation of the inflammatory mediator 5a and the membrane attack complex C5-9. Since everyone remembers the complement pathway so well (!) we have a helpful figure which shows how and where ravulizumab might help in IgAN.
Figure from Barratt et al Kidney Int 2023
Building on promising findings in the phase 2 SANCTUARY trial (JASN 2025), and with molecular support from sustained reductions in urinary biomarkers (Cammett et al CJASN 2026); the phase 3 I CAN trial (NEJM 2026) asked: can terminal complement blockade reduce proteinuria in patients with persistent disease despite standard care?
How was the study done?
They conducted a phase 3, multinational, randomized, double-blind, placebo-controlled trial enrolled adults with biopsy-confirmed IgA nephropathy, eGFR >30 ml/min/1.73 m², and persistent proteinuria: UPCR > 0.75 g/g or protein excretion > 1 g/day. All participants required meningococcal vaccination. Patients received intravenous ravulizumab or placebo every eight weeks alongside stable background therapy.
The primary endpoint was changed in 24-hour UPCR at week 34. All participants required meningococcal vaccination.
Figure S1, study design, from Barratt, NEJM 2026
What did it show?
The interim analysis included 352 patients, 176 per group. At week 34, UPCR decreased by 46.6% with ravulizumab versus 5.6% with placebo (95% CI, -53.2 to -39.0), corresponding to an adjusted UPCR 43.4% lower than placebo (99% CI, 30.1–54.2; P<.001).
The effect was apparent by week 10. An intention-to-treat sensitivity analysis produced an almost identical result, strengthening confidence that the primary finding was not dependent on the main analysis assumptions.
Urinary complement and injury biomarkers also decreased. In the safety population, adverse events occurred in 69.5% versus 75.8%, and serious adverse events in 4.6% versus 9.0%. Serious infections occurred in four patients per group. No meningococcal infections or deaths were reported.
Figure 1, Changes from Baseline in 24-hour UPCR, from Barratt, NEJM 2026
How should we interpret it?
The double-blind randomized design, prespecified interim analysis, international recruitment, contemporary background therapy, and low discontinuation strengthen the proteinuria finding. An intention-to-treat sensitivity analysis produced consistent results.
However, proteinuria reduction does not yet establish preservation of kidney function. Durability, eGFR effects, and longer-term safety require further follow-up. The absence of meningococcal infections in vaccinated participants does not exclude this known risk of C5 inhibition.
The trial cannot establish comparative effectiveness against other IgAN therapies or the benefits of combining them. Results for patients with eGFR 20–29 were not included, and applicability to children, transplant recipients, and patients with IgA vasculitis remains uncertain. Extensive sponsor involvement in trial conduct, analysis, and reporting also warrants consideration.
However, based on proteinuria, ravulizumab is already approved in the US (brand name Ultomiris), and it is already available in many places for its previous indications (aHUS, PNH, myasthenia, NMOSD). Based on its mechanism of action far distally to BAFF/APRIL, we are not confident that its GFR lowering effect will equal the GFR stabilization effect we see with BAFF/APRIL inhibition. While we are glad there are more options, it is not clear where ravulizumab (like iptacopan) will settle into in our battle against the most common glomerular disease.
What can we conclude?
Ravulizumab substantially reduced proteinuria in adults with IgA nephropathy receiving supportive therapy, with no major short-term safety imbalance observed. The conclusion remains unproven in long term kidney protection. The present list price is about an annual $500-600,000.
Efficacy and Safety of Upacicalcet in Hemodialysis Patients with Secondary Hyperparathyroidism
Two Randomized Clinical Trials
Jessica Kendrick, Markus Kettele, Myles Wolf,Snezana Pesic, Biserka Tirmenstajn-Jankovic, Steven Zeig, Aaron Camp, Ellie Copeland, BT Slingsby, Bastian Dehmel, Geoffrey Block
Why was the study done?
Calcimimetics are well-trodden ground. Cinacalcet lowered PTH more than 20 years ago (Block et al, NEJM, 2004), then missed its hard endpoint in EVOLVE (ITT HR 0.93, 95% CI 0.85-1.02) (EVOLVE trial investigators, NEJM 2012). Etelcalcetide moved the drug into the dialysis circuit and solved adherence. It did not solve nausea, and it brought more hypocalcemia than cinacalcet (Block et al, JAMA, 2017| Block et al, JAMA, 2017).
Upacicalcet is a small molecule, positive allosteric modulator of the calcium-sensing receptor, given IV after each session. Preclinical data suggest it loses agonist activity when extracellular calcium falls below the physiologic range, and a single session removes 79-100% of it. Japan approved it in 2021 (Hoy, Drugs, 2021) on the strength of a 24- week placebo-controlled phase 3 trial (Shigematsu et al, CJASN, 2023). PATH-1 and PATH-2 tested whether upacicalcet lowers iPTH more than placebo in a predominantly US hemodialysis population with moderate to severe secondary hyperparathyroidism. The protocol restricted changes to calcium supplements and active vitamin D sterols, so that the effect of upacicalcet could be estimated on its own.
How was the study done and what did it show?
PATH-1 and PATH-2 were identical phase 3, double blind trials run in parallel, each randomizing 2:1 to upacicalceet or placebo at 131 in the US, Bulgaria, Spain, Poland, Portugal, and Serbia (May 2023 to January 2025). Treatment lasted 27 weeks: 19 weeks of titration (25-300 mcg) followed by 8 weeks of stable dosing. The efficacy window was weeks 22-27. Eligible adults had iPTH 400-1500 pg/mL, cCA ≥ 8.3 mg/dL, and dialysate calcium ≥ 2.5 mEq/L. Cinacalcet users needed a 4-week washout. Calcium supplements, active vitamin D, and binders could not be changed unless medically necessary.
Figure 1. Participant disposition in PATH-1 and PATH-2, from Kendrick et al, JASN, 2026
The full analysis set was 768 patients (510 upacicalcet, 258 placebo). Mean age was 59 years, and median iPTH was 649-712 pg/mL. PATH-1 enrolled 82% of its patients in the US, and 38% were Black (20% in PATH-2). About 88% of PATH-1 and 70% of PATH-2 patients were on active vitamin D.
Patients who discontinued treatment counted as nonresponders, and the analysis was a stratified Cochran-Mantel-Haenszel test. A ≥ 30% fall in mean iPTH occurred in 42.1% vs 16.8% in PATH-1 (difference 25.3 percentage points, 95% CI 16.2-34.5) and 43.5% vs 17.4% in PATH-2 (26.1 points, 95% CI 17.4-34.8; both P<0.001).
Figure2. Strata-adjusted proportion of participants with ≥ 30% decrease from baseline in mean iPTH during the efficacy assessment period 922-27) in PATH-1 and PATH-2, from Kendrick et al, JASN, 2026
The key secondaries were consistent but modest. A ≥ 50% fall occurred in 27.2% vs 7.5% and 25.1% vs 4.3%, and mean iPTH of 150-300 pg/ml in 18.8% vs 8.3% and 17.3% vs 4.3%. Mean iPTH change was -32.7% vs -1.5% and -35% vs -0.9%. Effects were consistent across subgroups, and FGF23 fell (exploratory endpoint).
Supplemental Table 4. Key secondary iPTH endpoints, weeks 22-27, from Kendrick et al, JASN, 2026
Serious AEs were balanced (26 vs 24%; 23% vs 22%), and so were nausea (3% vs 2%; 7% vs 5%). Calcium was a different story. By central laboratory, cCa fell below 7.5 mg/dl in 31% vs 12% (PATH-1) and 45% vs 19% (PATH-2). It fell below 8.3 mg/dl in 86% of upacicalcet patients in both trials. Dose interruptions occurred in 44% vs 24% and 52% vs 27%. Investigators recorded symptomatic hypocalcemia in 0.8% and 2% of upacicalcet patients and in no placebo patients.
What does it mean?
Upacicalcet lowers PTH more than placebo does, same as in the Japanese study (Shigematsu et al, CJASN, 2023). What PATH adds is a less flattering effect size. Fewer than half of the patients reached a 30% reduction, and fewer than one in five reached 150-200 pg/ml. In the Japanese trial, 81% reached a ≥30% reduction (baseline IPTH roughly half as high; calcium carbonate allowed to creep up). With etelcalcetide vs placebo, the figure was 74-75%.
The authors blame the calcium-restrictive protocol, and they have a point: nearly 30% of patients could not up-titrate because of low calcium. That argument cuts both ways. If upacicalcet backs off on a low calcium, the patients with the worst disease may get the least conditions on a post-randomization variable that itself suppresses PTH. Across the same cCa quartiles, the placebo response climbs from 0% to 34.8%. This gradient therefore likely reflects, at least in part, the direct suppressive effect of serum calcium on PTH secretion rather than an upacicalcet effect hidden by the protocol. Background therapy also did not stay entirely constant: in PATH-2, the proportion of upacicalcet-treated patients using calcium supplements or calcium-containing binders rose during treatment, while it remained stable with placebo.
Supplemental figure 4. Use of calcium supplements or calcium-containing phosphate binders over time in PATH-1 and PATH-2, from Kendrick et al, JASN, 2026
The “asymptomatic hypocalcemia” label is carrying a lot of weight: nearly half of PATH-2 upacicalcet patients dropped below 7.5 mg/dl at least once. KDIGO 2017 tolerates mild, asymptomatic hypocalcemia (KDIGO, Kidney Int Suppl, 2017). A cCa below 7.5 mg/dl is not mild hypocalcemia. Symptoms were also judged by investigators, which makes them a safe safety measure. The authors note that comparing these rates with the roughly 7% symptomatic hypocalcemia seen with etelcalcetide means comparing across trials.
Beyond that, the trials ran only 27 weeks and measured biochemistry, not fractures, parathyroidectomy, CV events, or death. Between 22% and 36% of patients per arm stopped the treatment. Comparing with placebo in 2026 sidesteps the question prescribers will ask. Cinacalcet is generic, and since 2021 calcimimetics have been paid from the US dialysis base rate (CMS, 2020), so a new IV agent has to beat etelcalcetide on something. The sponsor funded the trials, employed two authors, and paid for medical writing (Note: a “129%” share on the top dose and a twice-listed PATH-2 analysis plan suggested the proofreading was rushed, too).
A calcimimetic that steps back when calcium falls sounds elegant. In PATH, it stepped back often enough that the real question is not whether it is safer than etelcalcitide, but whether, at equal safety, it does enough.
Pentoxifylline for Chronic Kidney Disease in People with Diabetes: A Meta-Analysis of Randomized Trials
Rajiv Agarwal, David J. Leehey, Sankar D. Navaneethan, Kristina M. Utzschneider, Bin Xing, Kimberly Carlson
DOI: 10.1093/ndt/gfag244
Why was the study done?
We are almost at remission (see story 8 from 2025 top stories) of Diabetic Kidney Disease (DKD) so do we need more agents? Especially with the newer GLP1RA related drugs coming online. However, even with RAS blockade, SGLT2 inhibitors, finerenone and semaglutide, DKD patients do still progress, and cost limits access to these drugs in many places. Also, everyone does not tolerate every drug - so more options are always better. Pentoxifylline is a cheap generic oral methylxanthine with anti-inflammatory and antifibrotic effects, tested in DKD for almost 40 years. We discussed the PREDIAN trial on NephJC back in 2016! Seven earlier meta-analyses reported lower albuminuria, however the authors say none of these previous ones reported prediction intervals, This one asks whether that result is actually reliable, whether enough evidence had accrued to settle the question, or formally looked at hard outcomes.
How was it done?
It’s a prospectively registered systematic review of RCTs of oral pentoxifylline added to standard care in adults with DKD. Comparators were placebo, no additional treatment, or an ACEi/ARB (kept as a separate stratum). Seven databases plus the WHO trials registry were searched to June 2026, with no language restriction. One reviewer screened and extracted, and a second verified every value. Risk of bias was rated per result with RoB 2, and certainty with GRADE.
Figure 1. PRISMA 2020 flow diagram of study selection. from Agarwal et al, NDT 2026
The co-primary surrogate outcomes were albuminuria (pooled as a ratio of geometric means across ACR, albumin excretion, protein excretion and PCR) and GFR change from baseline (primary analysis limited to trials of 12 months or longer). The primary hard outcome was ESKD (dialysis or transplant) or all-cause death. Safety outcomes were GI adverse events, withdrawal for adverse events, and serious adverse events. They used random-effects models with Hartung-Knapp adjustment, and added two things to every estimate: a 95% prediction interval (where a new trial would be expected to land) and a trial sequential analysis (TSA), which shows how much of the required sample has accrued.
What did it show?
34 studies were included and 32 contributed data. Most were small, single-center, short (3 to 6 months) and often unblinded, usually using 400 mg two or three times daily. Risk of bias was mostly high, driven by selective reporting.
Table 1. Characteristics of the trials contributing to the review from Agarwal et al, NDT 2026
Figure R1. Risk of bias, albuminuria and proteinuria results from Agarwal et al, NDT 2026
Figure R2. Risk of bias, kidney function results from Agarwal et al, NDT 2026
Albuminuria: 22 trials gave a ratio of means of 0.69 (95% CI 0.50 to 0.94), about a 31% reduction. Heterogeneity was extreme (I² 97%) and the prediction interval was 0.15 to 3.10, so a new trial could show an 85% reduction or a threefold increase. It depended on the comparator: against an ACEi/ARB the ratio was 0.94 (0.87 to 1.03), while as add-on therapy it was 0.62 (0.41 to 0.91). Removing four trials with data-quality concerns gave 0.80 (0.61 to 1.07). TSA showed 53% of the required information, with no boundary crossed.
Figure 2. Forest plot of the ratio of means for albuminuria from Agarwal et al, NDT 2026
GFR: Five trials and 375 patients (12 months or longer) gave +4.49 mL/min/1.73 m² (0.84 to 8.14), with a prediction interval of −4.25 to +13.23. Restricting to the two low or some-concerns risk of bias trials gave +2.96 (−15.34 to 21.26). The estimate rose with risk of bias, from +1.52 where concerns were minor to +7.52 where they were serious. TSA showed 11% of the required information.
Figure 3. Forest plot of the mean difference in glomerular filtration rate change from baseline from Agarwal et al, NDT 2026
Hard outcomes: 29 events in 593 patients (14 on pentoxifylline, 15 on control), with a risk ratio of 0.90 (0.46 to 1.77). That is 3% of the information needed.
Safety: GI adverse events were three times as common (RR 3.00; 1.94 to 4.64). Withdrawal for adverse events trended higher (1.58; 0.96 to 2.60). Serious adverse events were similar (0.83; 0.56 to 1.22). GRADE certainty was low for albuminuria and GFR, very low for ESKD or death, and moderate for GI tolerability.
What does it mean?
Pentoxifylline is a drug in search of an indication. Here, it probably lowers albuminuria on average, but the estimate is really fragile. The benefit mainly comes from some add-on trials that disagree with each other for reasons nobody could explain, and it shrinks as trial quality improves. The GFR signal is also similar, with a few small trials, and the biggest effect in the weakest ones. For kidney failure and death there is almost no data, so this is absence of evidence, not evidence of no effect. The GI side effects are the one firm finding. The authors call for an adequately powered, long-term hard-outcome trial, and the VA PTXRx trial is ongoing, with enrolment complete (Leehey et al NDT 2026: for baseline data). It will be interesting to see how it performs on a baseline of highish flozination (~ 50%) as well as a third on GLP1RAs. A few years ago, a derivative (lisofylline) was created with supposedly better tolerability, but that went nowhere.
A few things to keep in mind while reading this meta-analysis. , firstly, the evidence is quite old: 24 of 32 trials predate 2019, so we can’t tell whether it adds anything on top of SGLT2i, finerenone or GLP-1 RA. It is quite possible that with these agents (particularly flozins) on board, the effect of pentoxifylline may not be as huge - and be difficult to demonstrate. Secondly, mixed measures were used and ACR, albumin and protein excretion and PCR were pooled together. The log-scale values were reconstructed because no trial reported geometric means, and the GFR pool mixed MDRD, creatinine-cystatin C eGFR and creatinine clearance. Thirdly, 5 of the six trials were excluded for data-integrity concerns, identified after inspecting extracted data. Four more with data-quality concerns were kept, and removing them moves albuminuria from 0.69 to 0.80. Also, hard events were incidental, came from flow diagrams and adverse-event tables, were likely undercounted, and weren’t assessed for risk of bias.
Summaries by Akshaya Jayachandran Brian Rifkin,
Cristina Popa, Milagros Flores, Swapnil Hiremath